Efficacy and Safety of the Selective Sphingosine 1-Phosphate Receptor Modulator, Etrasimod, in Adult Patients With Eosinophilic Esophagitis: Primary Results From the Phase 2 VOYAGE Study

Introduction: Etrasimod is an investigational, oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator in development to treat immune-mediated inflammatory disorders. Etrasimod regulates lymphocyte egress from secondary lymphatic organs, and therefore may have promise in EoE (T-cell-mediated disease). Methods: VOYAGE (NCT04682639) is a phase 2 study with a 24-week (wk) randomized, double-blind, placebo-controlled treatment period, followed by a 28-wk extension period (ongoing), investigating the efficacy and safety of oral etrasimod 1 and 2 mg QD vs placebo (PBO) in adults with active EoE (Figure 1). The primary efficacy endpoint was the percentage change from baseline (BL) (%CFB) in esophageal peak eosinophil count (PEC) at Wk 16. Other efficacy endpoints assessed the effects of etrasimod on histological and endoscopic features and symptoms of EoE, and included the proportion of patients who achieved PEC < 15 and ≤ 6 eosinophils/high power field, the absolute CFB in EoE-Histology Scoring System (EoE-HSS) grade and stage scores, EoE-Endoscopic Reference Score (EREFS), Patient Global Impression of Severity (PGIS), and Dysphagia Symptom Questionnaire (DSQ) (overall and by BL dilation history) at Wk 24. We present the findings from the double-blind treatment period. Results: We randomized 108 patients with active EoE to etrasimod 2 mg (N=41), etrasimod 1 mg (N=39) or PBO (N=28) (Figure 1). In total, 47.2% of patients were female, and at BL, patients had had EoE for an average of 4.6 years with 55.6% having a history of esophageal dilation and 40.0% having prior corticosteroid treatment. Treatment with etrasimod 2 mg QD resulted in a 46.1% decrease from BL in PEC (PBO-adjusted) at Wk 16 (P=0.0103). There were also statistically significant reductions in %CFB in PEC at Wk 24, and reductions in absolute CFB in EoE-HSS grade and stage scores, EREFS, PGIS, and, in patients without BL dilation history, DSQ score (Table 1). In etrasimod 1 mg- vs PBO-treated patients, there were also statistically significant reductions in %CFB in PEC and absolute CFB in EoE-HSS grade and stage scores at Wk 24. There were no serious treatment-emergent adverse events (TEAEs) reported up to Wk 24; 2 patients discontinued due to TEAEs (Table 1). Conclusion: Etrasimod 2 mg QD met the primary histologic endpoint and significantly improved endoscopic features of EoE, overall symptom severity, and dysphagia (in patients without dilation history only) at Wk 24, and was well tolerated. This supports further evaluation of etrasimod in EoE.Figure 1.: Study Design for VOYAGE. [a] Randomization was stratified by BL history of esophageal dilation and continued use of a stable proton pump inhibitor therapy at study entry; [b] EoE symptom severity and daily dysphagia scores were captured by PGIS and DSQ e-diaries, respectively; esophageal PEC and EoE-HSS (from EGD with biopsy) were centrally read by expert pathologists blinded to treatment assignment. The EREFS was scored by the local endoscopist. %CFB, percentage change from baseline; BL, baseline; DSQ, Dysphagia Symptom Questionnaire; EGD, esophagogastroduodenoscopy; EoE, eosinophilic esophagitis; EREFS, EoE-Endoscopic Reference Score; EoE-HSS, eosinophilic esophagitis Histology Scoring System; N, number of patients in treatment group; PEC, peak eosinophil count; PGIS, Patient Global Impression of Severity; QD, once-daily; R, randomization. Table 1. - Change from Baseline [a] in PEC at Week 16 (Primary Endpoint), Additional Efficacy Endpoints at Week 24 and a Summary of TEAEs up to Week 24 in the VOYAGE Study Etrasimod 2 mg QD (N=41) Etrasimod 1 mg QD (N=39) PBO QD (N=28) Visit/endpoint Baseline value mean (SD) Change from baseline Mean difference from PBO P value Baseline value mean (SD) Change from baseline Mean difference from PBO P value Baseline value mean (SD) Change from baseline Week 16 PEC [b],[c] 116.5 (82.6) -38.3 (77.91) -46.10.0103 106.3 (83.3) 40.3 (269.93) 32.50.2861 116.3 (71.9) 7.8 (87.77) Proportion with PEC < 15 eos/HPF 22.0% 12.8% 0.0% Proportion with PEC ≤ 6 eos/HPF 12.2% 7.7% 0.0% Week 24 PEC 116.5 (82.6) -52.4 (59.66) -113.7<0.0001 106.3 (83.3) -27.4 (78.00) -88.70.0022 116.3 (71.9) 61.3 (143.45) EoE-HSS grade [d],[e] 0.4 (0.18) -0.2 (0.03) -0.21<0.0001 0.4 (0.19) -0.1 (0.03) -0.19<0.0001 0.4 (0.16) 0.05 (0.03) EoE-HSS stage [d],[e] 0.4 (0.20) -0.2 (0.03) -0.23<0.0001 0.4 (0.24) -0.2 (0.03) -0.2000.0001 0.4 (0.22) 0.03 (0.04) EREFS [d],[f] 3.7 (1.74) -1.3 (0.26) -0.910.0303 3.2 (1.59) -1.0 (0.26) -0.610.1473 4.3 (1.39) -0.4 (0.32) PGIS [d],[g] 2.4 (0.6) -0.7 (0.12) -0.480.0121 2.3 (0.5) -0.5 (0.11) -0.280.1312 2.5 (0.6) -0.2 (0.14) DSQ Overall [d],[h] 33.6 (12.9) -18.6 (2.64) -4.160.3061 32.0 (10.0) -15.7 (2.52) -1.290.7451 32.7 (10.3) -14.5 (3.08) History of dilation = Yes 34.9 (11.5) -10.8 (4.40) 0.620.8992 31.6 (9.4) -9.3 (4.22) 2.120.6572 37.8 (8.5) -11.4 (5.10) History of dilation = No 32.2 (14.5) -21.6 (3.83) -11.950.0311 32.5 (11.2) -16.5 (3.82) -6.840.2014 26.9 (9.2) -9.6 (4.70) Proportion with PEC < 15 eos/HPF 31.7% 30.8% 0.0% Proportion with PEC ≤ 6 eos/HPF 24.4% 15.4% 0.0% Summary of TEAEs up to Week 24 in the VOAYGE study, n (%) [i] Etrasimod 2 mg QD (N=41) Etrasimod 1 mg QD (N=39) PBO QD (N=28) All causality TEAEs [j],[k] 29 (70.7) 27 (69.2) 21 (75.0) Serious TEAEs [l] 0 (0.0) 0 (0.0) 0 (0.0) TEAEs leading to study treatment discontinuation 1 (2.4) [m] 0 (0.0) 1 (3.6) [n] TEAEs occurring in ≥ 10% of patients [o] 6 (14.6) 3 (7.7) 3 (10.7) Nausea 4 (9.8) 4 (10.3) 1 (3.6) Dizziness 3 (7.3) 4 (10.3) 5 (17.9) COVID-19 1 (2.4) 1 (2.6) 5 (17.9) Esophageal food impaction EoE 0 (0.0) 1 (2.6) 3 (10.7) TEAEs leading to death 0 (0.0) 0 (0.0) 0 (0.0) [a] %CFB (mean [SD]) calculated for PEC, and absolute change from baseline (LS mean [SE]) calculated for DSQ, PGIS, EOE-HSS grade and stage, and EREFS. All PBO-adjusted differences from PBO are expressed as LS mean, except %CFB in PEC, which is expressed as the mean difference; [b] P-values are from an ANCOVA model for rank score of %CFB including factors for treatment group, baseline history of esophageal dilation (Yes/No), concurrent PPI therapy (Yes/No), and baseline eosinophil PEC (eos/HPF) as a covariate; [c] Full analysis set; includes all randomized patients who receive at least one dose of study treatment; [d] P-values are from a linear mixed effects model for change from baseline including factors for treatment group, visit, interaction of treatment-by-visit, baseline history of esophageal dilation (Yes/No), concurrent PPI therapy (Yes/No), and baseline score as a covariate; [e] Grade and stage score ranges from 0–1; [f] Score ranges from 0–9; [g] Score ranges from 0–4; [h] Score ranges from 0–84; [i] Safety analysis set; includes all patients who were randomized and received at least one dose of study treatment; [j] Severity was classified using CTCAE, version 5.0, i.e., Grade 1 for mild, Grade 2 for moderate, Grade 3 for severe, Grade 4 for life-threatening, Grade 5 for death related to AE; the majority of AEs were Grade 1 or 2; [k] First-dose, transient HR reductions and cardiac conduction aberrations are known on-target effects of sphingosine 1-phosphate receptor modulators. Bradycardia events were reported by 3 patients. One event occurred on Day 1 in a patient taking etrasimod 2 mg QD and was classed as Grade 2; one event occurred on Day 3 in a patient taking etrasimod 2 mg QD and was classed as Grade 1; one event occurred at the Week 24 visit when the patient transitioned from placebo treatment to blinded etrasimod 1 mg or 2 mg QD (ie. Day 1 of etrasimod) and was classed as Grade 1. Two cases associated with the first etrasimod dose (asymptomatic with unremarkable EKG findings) resolved without any interventions at Hour 5 of the cardiac monitor procedure. The third case (without documented HR measurement) was associated with dizziness and nausea and was reported on Study Day 3. The patient continued study treatment and all AEs resolved without interventions on Study Day 23; [l] Where seriousness was not entered/missing, the event was classified as serious; [m] Balance disorder, Grade 2; [n] Dysphagia, Grade 2; [o] TEAEs occurred in ≥ 10% of patients in at least one treatment group. %CFB, percentage change from baseline; AE, adverse event; ANCOVA, analysis of covariance; COVID-19, Coronavirus Disease 2019; CTCAE, common terminology criteria for adverse events; DSQ, Dysphagia Symptom Questionnaire; EKG, electrocardiogram; EoE, eosinophilic esophagitis; EoE-HSS, eosinophilic esophagitis Histology Scoring System; eos, eosinophils; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; HPF, high power field; HR, heart rate; LS, least squares; n, number of patients with event; N, number of patients in the treatment group; PBO, placebo; PEC, peak eosinophil count; PGIS, Patient Global Impression of Severity; PPI, proton pump inhibitor; QD, once-daily; SD, standard deviation; TEAE, treatment-emergent adverse event.